const pptxgen = require("pptxgenjs");

const pres = new pptxgen();
pres.layout = "LAYOUT_WIDE";
pres.title = "Newly Approved Diabetes Drugs Worldwide (2015–2025)";
pres.author = "Orris Medical";

// ─── COLOR PALETTE ───────────────────────────────────────────────────────────
const C = {
  navy:     "0A2342",   // dominant dark background
  teal:     "1ABC9C",   // accent / highlights
  sky:      "2980B9",   // secondary blue
  white:    "FFFFFF",
  offWhite: "EAF4FC",
  gray:     "B0C4D8",
  red:      "E74C3C",
  orange:   "E67E22",
  green:    "27AE60",
  purple:   "8E44AD",
  yellow:   "F1C40F",
  darkCard: "102A4C",
  midCard:  "163556",
};

// ─── HELPER FUNCTIONS ─────────────────────────────────────────────────────────
function addSlideBg(slide, color = C.navy) {
  slide.background = { color };
}

function sectionHeader(slide, text) {
  slide.addShape(pres.ShapeType.rect, {
    x: 0, y: 0, w: 13.3, h: 0.6, fill: { color: C.teal }, line: { color: C.teal }
  });
  slide.addText(text, {
    x: 0.3, y: 0, w: 12.7, h: 0.6,
    fontSize: 14, bold: true, color: C.navy, valign: "middle", margin: 0
  });
}

function titleBox(slide, title, subtitle) {
  slide.addText(title, {
    x: 0.5, y: 1.5, w: 12.3, h: 1.1,
    fontSize: 36, bold: true, color: C.white, align: "center"
  });
  slide.addText(subtitle, {
    x: 0.5, y: 2.7, w: 12.3, h: 0.6,
    fontSize: 18, color: C.teal, align: "center", italic: true
  });
}

function card(slide, x, y, w, h, headingText, headingColor, bodyLines) {
  // Card background
  slide.addShape(pres.ShapeType.roundRect, {
    x, y, w, h,
    fill: { color: C.darkCard },
    line: { color: C.teal, width: 1.5 },
    rectRadius: 0.12
  });
  // Heading bar
  slide.addShape(pres.ShapeType.roundRect, {
    x, y, w, h: 0.44,
    fill: { color: headingColor || C.teal },
    line: { color: headingColor || C.teal },
    rectRadius: 0.12
  });
  slide.addText(headingText, {
    x: x + 0.12, y: y, w: w - 0.24, h: 0.44,
    fontSize: 12, bold: true, color: C.navy, valign: "middle", margin: 0
  });
  // Body
  const items = bodyLines.map((line, i) => ({
    text: line,
    options: { bullet: { code: "2022" }, color: C.offWhite, fontSize: 10.5, breakLine: i < bodyLines.length - 1 }
  }));
  slide.addText(items, {
    x: x + 0.12, y: y + 0.5, w: w - 0.24, h: h - 0.58,
    valign: "top", lineSpacingMultiple: 1.25
  });
}

function drugSlide(drugName, drugBrand, approvalYear, approvalAgency, classText, classColor, mechanism, drawbacks, footnote) {
  const slide = pres.addSlide();
  addSlideBg(slide);

  // Top accent stripe
  slide.addShape(pres.ShapeType.rect, {
    x: 0, y: 0, w: 13.3, h: 0.55,
    fill: { color: classColor }, line: { color: classColor }
  });
  slide.addText(`${classText}  ·  Approved ${approvalYear} (${approvalAgency})`, {
    x: 0.3, y: 0, w: 12.7, h: 0.55,
    fontSize: 13, bold: true, color: C.navy, valign: "middle", margin: 0
  });

  // Drug name block
  slide.addText(drugName, {
    x: 0.4, y: 0.7, w: 9, h: 0.72,
    fontSize: 30, bold: true, color: C.white, margin: 0
  });
  slide.addText(`Brand: ${drugBrand}`, {
    x: 0.4, y: 1.42, w: 9, h: 0.36,
    fontSize: 13, italic: true, color: C.teal, margin: 0
  });

  // Mechanism card
  card(slide, 0.3, 1.9, 6.1, 2.85, "⚙  Mechanism of Action", C.sky, mechanism);

  // Drawbacks card
  card(slide, 6.7, 1.9, 6.0, 2.85, "⚠  Main Drawbacks / Limitations", C.red, drawbacks);

  // Footnote
  if (footnote) {
    slide.addText(footnote, {
      x: 0.3, y: 5.1, w: 12.7, h: 0.35,
      fontSize: 9, color: C.gray, italic: true
    });
  }
  return slide;
}

// ─── SLIDE 1: TITLE ──────────────────────────────────────────────────────────
{
  const slide = pres.addSlide();
  addSlideBg(slide);

  // Big circle accent
  slide.addShape(pres.ShapeType.ellipse, {
    x: 9.5, y: -1.5, w: 6, h: 6,
    fill: { color: "0F3460" }, line: { color: "0F3460" }
  });
  slide.addShape(pres.ShapeType.ellipse, {
    x: -2, y: 3, w: 5, h: 5,
    fill: { color: "0F3460" }, line: { color: "0F3460" }
  });

  // Teal top stripe
  slide.addShape(pres.ShapeType.rect, {
    x: 0, y: 0, w: 13.3, h: 0.08,
    fill: { color: C.teal }, line: { color: C.teal }
  });
  slide.addShape(pres.ShapeType.rect, {
    x: 0, y: 5.42, w: 13.3, h: 0.08,
    fill: { color: C.teal }, line: { color: C.teal }
  });

  slide.addText("Newly Approved Diabetes Drugs", {
    x: 0.5, y: 0.7, w: 12.3, h: 1.1,
    fontSize: 40, bold: true, color: C.white, align: "center"
  });
  slide.addText("Worldwide  |  2015 – 2025", {
    x: 0.5, y: 1.85, w: 12.3, h: 0.6,
    fontSize: 22, color: C.teal, align: "center", italic: true
  });

  // Divider
  slide.addShape(pres.ShapeType.line, {
    x: 3, y: 2.58, w: 7.3, h: 0,
    line: { color: C.teal, width: 1.5 }
  });

  slide.addText("Mechanisms of Action  ·  Clinical Use  ·  Drawbacks", {
    x: 0.5, y: 2.7, w: 12.3, h: 0.45,
    fontSize: 14, color: C.gray, align: "center"
  });

  // Drug class pills
  const classes = [
    { text: "GLP-1 RAs", color: C.green },
    { text: "SGLT2 Inhibitors", color: C.sky },
    { text: "DPP-4 Inhibitors", color: C.purple },
    { text: "Insulins", color: C.orange },
    { text: "Dual Agonists", color: C.teal },
    { text: "Others", color: C.red },
  ];
  const pw = 1.8, gap = 0.22, startX = (13.3 - (classes.length * pw + (classes.length - 1) * gap)) / 2;
  classes.forEach((cls, i) => {
    const cx = startX + i * (pw + gap);
    slide.addShape(pres.ShapeType.roundRect, {
      x: cx, y: 3.3, w: pw, h: 0.4,
      fill: { color: cls.color }, line: { color: cls.color }, rectRadius: 0.2
    });
    slide.addText(cls.text, {
      x: cx, y: 3.3, w: pw, h: 0.4,
      fontSize: 10.5, bold: true, color: C.navy, align: "center", valign: "middle", margin: 0
    });
  });

  slide.addText("Prepared by Orris Medical Intelligence  |  May 2026", {
    x: 0.5, y: 5.0, w: 12.3, h: 0.3,
    fontSize: 9, color: C.gray, align: "center", italic: true
  });
}

// ─── SLIDE 2: OVERVIEW TABLE ──────────────────────────────────────────────────
{
  const slide = pres.addSlide();
  addSlideBg(slide);
  sectionHeader(slide, "Drug Approval Overview  |  2015–2025  |  FDA & EMA");

  slide.addText("At-a-Glance: Key Approvals by Drug Class", {
    x: 0.3, y: 0.7, w: 12.7, h: 0.45,
    fontSize: 18, bold: true, color: C.white
  });

  const headers = ["Drug (Brand)", "Class", "Year", "Agency", "Type"];
  const rows = [
    ["Insulin degludec (Tresiba)", "Basal Insulin", "2015", "FDA/EMA", "T1 & T2DM"],
    ["Albiglutide (Tanzeum)", "GLP-1 RA", "2014/2015", "FDA/EMA", "T2DM"],
    ["Dulaglutide (Trulicity)", "GLP-1 RA", "2014/2015", "FDA/EMA", "T2DM"],
    ["Empagliflozin (Jardiance)", "SGLT2i", "2014/2015", "FDA/EMA", "T2DM"],
    ["Canagliflozin (Invokana)", "SGLT2i", "2013/2014", "FDA/EMA", "T2DM"],
    ["Dapagliflozin (Farxiga)", "SGLT2i", "2014", "FDA", "T2DM/T1DM"],
    ["Semaglutide SC (Ozempic)", "GLP-1 RA", "2017", "FDA", "T2DM"],
    ["Semaglutide oral (Rybelsus)", "GLP-1 RA", "2019", "FDA", "T2DM"],
    ["Tirzepatide (Mounjaro)", "GIP/GLP-1 DA", "2022", "FDA", "T2DM"],
    ["Teplizumab (Tzield)", "Anti-CD3 mAb", "2022", "FDA", "T1DM (delay)"],
    ["Insulin icodec", "Once-weekly insulin", "2023", "EMA", "T2DM"],
    ["Retatrutide", "GIP/GLP-1/Gcg", "2024*", "Phase 3", "T2DM/Obesity"],
  ];

  const colW = [3.4, 2.2, 1.1, 1.2, 1.4];
  const colX = [0.25, 3.65, 5.85, 6.95, 8.15];
  const rowH = 0.33;
  const startY = 1.25;

  // Header row
  headers.forEach((h, ci) => {
    slide.addShape(pres.ShapeType.rect, {
      x: colX[ci], y: startY, w: colW[ci], h: rowH,
      fill: { color: C.teal }, line: { color: C.navy }
    });
    slide.addText(h, {
      x: colX[ci] + 0.05, y: startY, w: colW[ci] - 0.1, h: rowH,
      fontSize: 11, bold: true, color: C.navy, valign: "middle", margin: 0
    });
  });

  rows.forEach((row, ri) => {
    const y = startY + (ri + 1) * rowH;
    const bg = ri % 2 === 0 ? C.darkCard : C.midCard;
    row.forEach((cell, ci) => {
      slide.addShape(pres.ShapeType.rect, {
        x: colX[ci], y, w: colW[ci], h: rowH,
        fill: { color: bg }, line: { color: C.navy, width: 0.5 }
      });
      slide.addText(cell, {
        x: colX[ci] + 0.07, y, w: colW[ci] - 0.1, h: rowH,
        fontSize: 9.5, color: C.offWhite, valign: "middle", margin: 0
      });
    });
  });

  // Side legend
  const legend = [
    { label: "GLP-1 RA", color: C.green, desc: "GLP-1 Receptor Agonist" },
    { label: "SGLT2i", color: C.sky, desc: "Sodium-Glucose Co-transporter 2 Inhibitor" },
    { label: "DPP-4i", color: C.purple, desc: "Dipeptidyl Peptidase-4 Inhibitor" },
    { label: "GIP/GLP-1 DA", color: C.teal, desc: "Dual GIP + GLP-1 Agonist" },
    { label: "mAb", color: C.orange, desc: "Monoclonal Antibody" },
  ];
  slide.addText("Class Legend", {
    x: 9.6, y: 1.25, w: 3.4, h: 0.33,
    fontSize: 11, bold: true, color: C.teal, valign: "middle"
  });
  legend.forEach((l, i) => {
    const ly = 1.6 + i * 0.6;
    slide.addShape(pres.ShapeType.roundRect, {
      x: 9.6, y: ly, w: 0.8, h: 0.32,
      fill: { color: l.color }, line: { color: l.color }, rectRadius: 0.1
    });
    slide.addText(l.label, {
      x: 9.6, y: ly, w: 0.8, h: 0.32,
      fontSize: 8.5, bold: true, color: C.navy, align: "center", valign: "middle", margin: 0
    });
    slide.addText(l.desc, {
      x: 10.45, y: ly, w: 2.6, h: 0.32,
      fontSize: 8.5, color: C.gray, valign: "middle", margin: 0
    });
  });

  slide.addText("*Retatrutide: Phase 3 completed; regulatory submission pending as of 2025", {
    x: 0.3, y: 5.1, w: 12.7, h: 0.3,
    fontSize: 8.5, italic: true, color: C.gray
  });
}

// ─── DRUG SLIDES ──────────────────────────────────────────────────────────────

// 1. SGLT2 Inhibitors class intro
{
  const slide = pres.addSlide();
  addSlideBg(slide);
  slide.addShape(pres.ShapeType.rect, {
    x: 0, y: 0, w: 13.3, h: 5.5,
    fill: { color: C.navy }, line: { color: C.navy }
  });
  slide.addShape(pres.ShapeType.rect, {
    x: 0, y: 0, w: 0.18, h: 5.5,
    fill: { color: C.sky }, line: { color: C.sky }
  });
  slide.addText("SGLT2 INHIBITORS", {
    x: 0.5, y: 1.3, w: 12.3, h: 1.0,
    fontSize: 46, bold: true, color: C.sky, align: "center", charSpacing: 6
  });
  slide.addText("Sodium-Glucose Co-transporter 2 Inhibitors", {
    x: 0.5, y: 2.4, w: 12.3, h: 0.5,
    fontSize: 18, color: C.white, align: "center", italic: true
  });
  slide.addShape(pres.ShapeType.line, {
    x: 3, y: 3.05, w: 7.3, h: 0,
    line: { color: C.sky, width: 1.5 }
  });
  slide.addText("Empagliflozin  ·  Canagliflozin  ·  Dapagliflozin  ·  Ertugliflozin", {
    x: 0.5, y: 3.2, w: 12.3, h: 0.4,
    fontSize: 14, color: C.gray, align: "center"
  });
}

// 2. Empagliflozin
drugSlide(
  "Empagliflozin", "Jardiance",
  "2014 (EMA) / 2014 (FDA)", "FDA & EMA",
  "SGLT2 Inhibitor", C.sky,
  [
    "Selectively inhibits SGLT2 in proximal renal tubule",
    "Blocks ~90% of filtered glucose reabsorption",
    "Causes urinary glucose excretion (~70g/day)",
    "Reduces plasma glucose in insulin-independent manner",
    "Also lowers blood pressure via osmotic diuresis & natriuresis",
    "Cardioprotective via ketone body utilization (EMPA-REG OUTCOME trial)"
  ],
  [
    "Urinary tract infections (UTIs) — increased risk",
    "Genital mycotic infections (especially women)",
    "Diabetic ketoacidosis (DKA) — even with normal glucose (euglycemic DKA)",
    "Fournier's gangrene (rare but serious perineal necrotizing fasciitis)",
    "Volume depletion / hypotension — caution in elderly",
    "Reduced efficacy in eGFR <30 mL/min/1.73m²",
    "Lower limb amputations — not confirmed for empagliflozin vs canagliflozin"
  ],
  "EMPA-REG OUTCOME trial (2015): 14% relative risk reduction in MACE; 35% reduction in HF hospitalization"
);

// 3. Canagliflozin
drugSlide(
  "Canagliflozin", "Invokana",
  "2013 (FDA) / 2014 (EMA)", "FDA & EMA",
  "SGLT2 Inhibitor", C.sky,
  [
    "Inhibits SGLT2 and (partly) SGLT1 in kidney and intestine",
    "Reduces renal glucose threshold → increased glucosuria",
    "Dual action reduces postprandial glucose via SGLT1 intestinal inhibition",
    "Modest weight loss via caloric loss in urine",
    "Lowers systolic BP by 3–5 mmHg (diuretic + natriuretic effects)",
    "Reduces intraglomerular pressure → nephroprotective (CREDENCE trial)"
  ],
  [
    "Increased risk of lower limb amputations (toe/foot) — FDA Black Box Warning",
    "Bone fracture risk — inhibits bone resorption pathways, alters phosphate/Ca²⁺",
    "Genital yeast infections — very common (10–15% in women)",
    "Euglycemic DKA — particularly risk in T1DM off-label use",
    "Acute kidney injury risk — volume depletion mediated",
    "Urinary tract infections and Fournier's gangrene (rare)",
    "Hypercholesterolemia — LDL increase ~4-8%"
  ],
  "CANVAS trial & CREDENCE trial: Renal protection in DKD; FDA amputation Black Box Warning added 2017"
);

// 4. Dapagliflozin
drugSlide(
  "Dapagliflozin", "Farxiga / Forxiga",
  "2012 (EMA) / 2014 (FDA)", "FDA & EMA",
  "SGLT2 Inhibitor", C.sky,
  [
    "Highly selective SGLT2 inhibitor (>1200-fold selectivity over SGLT1)",
    "Inhibits ~40-50% of renal glucose reabsorption",
    "Increases urinary glucose and sodium excretion",
    "Reduces HbA1c by ~0.5–0.9% from baseline",
    "FDA-approved for T1DM (as adjunct to insulin) in 2019",
    "Cardioprotective in HFrEF (DAPA-HF trial) — first SGLT2i approved for heart failure without diabetes"
  ],
  [
    "Genital mycotic infections — most common side effect (~8%)",
    "Urinary frequency — polyuria from glucosuria",
    "Euglycemic DKA — higher concern in T1DM use (FDA warning)",
    "Bladder cancer signal — initial concern from FDA (DECLARE-TIMI 58 trial not confirmed)",
    "Dehydration / hypotension — especially with loop diuretics",
    "Reduced efficacy in renal impairment (eGFR <45)",
    "Risk of Fournier's gangrene — FDA black box 2018"
  ],
  "DAPA-HF trial (2019): 26% relative risk reduction in HF worsening/CV death regardless of T2DM status"
);

// 5. GLP-1 RA class intro
{
  const slide = pres.addSlide();
  addSlideBg(slide);
  slide.addShape(pres.ShapeType.rect, {
    x: 0, y: 0, w: 0.18, h: 5.5,
    fill: { color: C.green }, line: { color: C.green }
  });
  slide.addText("GLP-1 RECEPTOR AGONISTS", {
    x: 0.5, y: 1.3, w: 12.3, h: 1.0,
    fontSize: 38, bold: true, color: C.green, align: "center", charSpacing: 4
  });
  slide.addText("Glucagon-Like Peptide-1 Receptor Agonists", {
    x: 0.5, y: 2.4, w: 12.3, h: 0.5,
    fontSize: 18, color: C.white, align: "center", italic: true
  });
  slide.addShape(pres.ShapeType.line, {
    x: 3, y: 3.05, w: 7.3, h: 0,
    line: { color: C.green, width: 1.5 }
  });
  slide.addText("Dulaglutide  ·  Semaglutide (SC & Oral)  ·  Liraglutide  ·  Albiglutide  ·  Efpeglenatide", {
    x: 0.5, y: 3.2, w: 12.3, h: 0.4,
    fontSize: 13, color: C.gray, align: "center"
  });
}

// 6. Dulaglutide
drugSlide(
  "Dulaglutide", "Trulicity",
  "2014", "FDA & EMA",
  "GLP-1 Receptor Agonist", C.green,
  [
    "GLP-1 receptor agonist — mimics endogenous incretin hormone GLP-1",
    "Stimulates glucose-dependent insulin secretion (↓ hypoglycemia risk)",
    "Suppresses glucagon secretion in postprandial state",
    "Slows gastric emptying → reduced postprandial glucose excursions",
    "Central appetite suppression → weight loss (2–4 kg average)",
    "Once-weekly SC injection — long half-life via Fc fusion protein",
    "CV benefit: REWIND trial — 12% reduction in MACE vs placebo"
  ],
  [
    "Nausea, vomiting, diarrhea — dose-dependent GI side effects (up to 20%)",
    "Risk of acute pancreatitis — FDA warning (causality debated)",
    "Contraindicated with personal/family history of medullary thyroid carcinoma (MTC)",
    "MEN2 syndrome contraindication — thyroid C-cell tumor risk (rodent data)",
    "Injection site reactions — subcutaneous use only",
    "Heart rate increase of 2–4 bpm",
    "Limited use in severe GI disease, gastroparesis",
    "Very expensive vs older agents"
  ],
  "REWIND trial (2019): Reduced MACE in T2DM patients with mixed CV risk profile (primary & secondary prevention)"
);

// 7. Semaglutide SC (Ozempic)
drugSlide(
  "Semaglutide SC", "Ozempic (T2DM) / Wegovy (Obesity)",
  "2017 (FDA) / 2018 (EMA)", "FDA & EMA",
  "GLP-1 Receptor Agonist", C.green,
  [
    "Human GLP-1 analogue with 94% sequence homology to native GLP-1",
    "C18 fatty acid modification allows albumin binding → 168h half-life",
    "Stimulates glucose-dependent insulin release from β-cells",
    "Suppresses α-cell glucagon secretion",
    "Potent gastric emptying delay → postprandial glucose control",
    "Strong CNS appetite suppression via hypothalamic GLP-1R → 5–14% weight loss",
    "SUSTAIN-6 & LEADER trials: Superior MACE reduction vs placebo"
  ],
  [
    "GI side effects — nausea in ~20%, vomiting in ~9%, diarrhea in ~9%",
    "Gallbladder disease — cholelithiasis (rapid weight loss effect)",
    "Thyroid C-cell tumors in rodent models — contraindicated in MTC/MEN2",
    "Acute pancreatitis — FDA warning (rare, ~0.4%)",
    "Diabetic retinopathy complications — SUSTAIN-6 showed 76% worsening risk (rapid HbA1c drops)",
    "Injection-site reactions (erythema, nodules)",
    "Risk of malnutrition/sarcopenia with aggressive weight loss",
    "Once-weekly injection remains a barrier for needle-phobic patients"
  ],
  "SUSTAIN-6 (2016): 26% MACE reduction. STEP program (2021): 15% body weight reduction for obesity indication"
);

// 8. Semaglutide Oral
drugSlide(
  "Oral Semaglutide", "Rybelsus",
  "2019 (FDA) / 2020 (EMA)", "FDA & EMA",
  "GLP-1 Receptor Agonist (Oral)", C.green,
  [
    "First oral GLP-1 receptor agonist approved for T2DM",
    "Uses SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) as absorption enhancer",
    "SNAC buffers gastric pH locally → protects semaglutide from proteolysis",
    "Absorbed across gastric mucosa — rapid absorption within 1 hour of dosing",
    "Same GLP-1R agonism as injectable: insulin stimulation, glucagon suppression",
    "HbA1c reduction: 1.0–1.4% vs placebo",
    "Weight loss: 2–5 kg over 26 weeks (less than SC form)"
  ],
  [
    "Strict fasting requirement — must be taken on empty stomach with ≤4 oz water, then fast 30 mins",
    "Highly variable bioavailability (0.4–1%) — food dramatically reduces absorption",
    "GI side effects similar to SC form: nausea, vomiting, diarrhea",
    "Drug interactions — must not be taken with other oral medications simultaneously",
    "Less weight loss than SC semaglutide or tirzepatide",
    "Same thyroid/pancreatitis concerns as injectable form",
    "Higher pill burden versus other oral antidiabetics"
  ],
  "PIONEER 6 (2019): Non-inferior to placebo for MACE; trend toward CV benefit not statistically significant"
);

// 9. DPP-4 Inhibitors class intro
{
  const slide = pres.addSlide();
  addSlideBg(slide);
  slide.addShape(pres.ShapeType.rect, {
    x: 0, y: 0, w: 0.18, h: 5.5,
    fill: { color: C.purple }, line: { color: C.purple }
  });
  slide.addText("DPP-4 INHIBITORS", {
    x: 0.5, y: 1.6, w: 12.3, h: 0.9,
    fontSize: 44, bold: true, color: C.purple, align: "center", charSpacing: 5
  });
  slide.addText("Dipeptidyl Peptidase-4 Inhibitors  (Gliptins)", {
    x: 0.5, y: 2.6, w: 12.3, h: 0.5,
    fontSize: 18, color: C.white, align: "center", italic: true
  });
  slide.addShape(pres.ShapeType.line, {
    x: 3, y: 3.25, w: 7.3, h: 0,
    line: { color: C.purple, width: 1.5 }
  });
  slide.addText("Alogliptin  ·  Trelagliptin  ·  Omarigliptin  ·  Saxagliptin (2009)  ·  Linagliptin (2011)", {
    x: 0.5, y: 3.4, w: 12.3, h: 0.4,
    fontSize: 13, color: C.gray, align: "center"
  });
}

// 10. Alogliptin
drugSlide(
  "Alogliptin", "Nesina / Vipidia",
  "2013 (FDA) / 2013 (EMA)", "FDA & EMA",
  "DPP-4 Inhibitor", C.purple,
  [
    "Highly selective competitive inhibitor of DPP-4 enzyme",
    "DPP-4 normally degrades incretins (GLP-1, GIP) within 2 minutes",
    "Inhibition increases endogenous GLP-1 and GIP levels 2–3 fold",
    "Enhanced incretin effect → glucose-dependent insulin secretion",
    "Suppresses inappropriate glucagon secretion in postprandial state",
    "Weight-neutral — does not cause weight gain or significant weight loss",
    "Low hypoglycemia risk when used as monotherapy",
    "Renal dose adjustment required but usable in CKD"
  ],
  [
    "Modest HbA1c reduction (0.5–0.8%) — less potent than GLP-1 RAs",
    "Increased risk of heart failure hospitalization (EXAMINE trial signal — borderline significant)",
    "Nasopharyngitis and upper respiratory tract infections (~6%)",
    "Rare severe allergic reactions — angioedema, anaphylaxis, Stevens-Johnson syndrome",
    "Hepatotoxicity — rare but FDA post-marketing safety review",
    "Acute pancreatitis — class effect; FDA warning",
    "Arthralgia — class effect, sometimes severe/disabling",
    "No proven cardiovascular mortality benefit"
  ],
  "EXAMINE trial (2013): Non-inferior to placebo for MACE; no CV mortality benefit; HHF signal at upper CI boundary"
);

// 11. Tirzepatide
{
  const slide = pres.addSlide();
  addSlideBg(slide);

  slide.addShape(pres.ShapeType.rect, {
    x: 0, y: 0, w: 13.3, h: 0.55,
    fill: { color: C.teal }, line: { color: C.teal }
  });
  slide.addText("GIP/GLP-1 Dual Agonist  ·  First-in-Class  ·  Approved May 2022 (FDA)", {
    x: 0.3, y: 0, w: 12.7, h: 0.55,
    fontSize: 13, bold: true, color: C.navy, valign: "middle", margin: 0
  });

  slide.addText("Tirzepatide", {
    x: 0.4, y: 0.7, w: 9, h: 0.72,
    fontSize: 30, bold: true, color: C.white, margin: 0
  });
  slide.addText("Brand: Mounjaro (T2DM) / Zepbound (Obesity)", {
    x: 0.4, y: 1.42, w: 9, h: 0.36,
    fontSize: 13, italic: true, color: C.teal, margin: 0
  });

  // Mechanism
  card(slide, 0.3, 1.9, 6.1, 3.0, "⚙  Mechanism of Action", C.sky, [
    "Novel 'twincretin' — single peptide activating both GIP and GLP-1 receptors",
    "GLP-1R activation: glucose-dependent insulin release, glucagon suppression, slowed gastric emptying",
    "GIPR activation: enhances insulin secretion, promotes adipocyte lipid utilization",
    "GIP component may reduce GI side effects vs pure GLP-1 RAs",
    "Potent HbA1c reduction: up to 2.3% in SURPASS trials — unprecedented",
    "Weight loss: 15–22.5% body weight (SURMOUNT trials) — best-in-class",
    "Once-weekly subcutaneous injection (2.5 → 5 → 10 → 15 mg escalation)"
  ]);

  // Drawbacks
  card(slide, 6.7, 1.9, 6.0, 3.0, "⚠  Main Drawbacks / Limitations", C.red, [
    "GI side effects: nausea (17%), diarrhea (17%), vomiting (9%) — most common reason for discontinuation",
    "Thyroid C-cell tumor concern — contraindicated in MTC/MEN2 (class effect with GLP-1 RA component)",
    "Gallbladder disease: cholelithiasis/cholecystitis (0.6–1%)",
    "Acute pancreatitis — post-marketing surveillance ongoing",
    "Heart rate increase ~2–4 bpm",
    "Very high cost ($1,000/month in US without insurance) — access barrier",
    "Muscle mass loss (sarcopenia risk) with rapid weight loss",
    "Long-term cardiovascular outcome trial (SURPASS-CVOT) data still maturing"
  ]);

  slide.addText("SURPASS-2 (2021): Tirzepatide 15 mg lowered HbA1c by 2.3% and weight by 13.1 kg vs semaglutide 1 mg", {
    x: 0.3, y: 5.0, w: 12.7, h: 0.35,
    fontSize: 9, color: C.gray, italic: true
  });
}

// 12. Teplizumab (T1DM)
drugSlide(
  "Teplizumab", "Tzield",
  "November 2022 (FDA)", "FDA (first & only)",
  "Anti-CD3 Monoclonal Antibody", C.orange,
  [
    "First disease-modifying drug approved for Type 1 Diabetes prevention",
    "Anti-CD3 monoclonal antibody targeting T-lymphocyte surface receptor CD3",
    "Modulates autoreactive T-cell destruction of pancreatic β-cells",
    "Induces 'exhausted' regulatory T-cell phenotype that halts autoimmune attack",
    "Approved to delay Stage 3 T1DM onset in at-risk individuals (Stage 2 T1DM)",
    "14-day IV infusion course",
    "Landmark TrialNet study: delayed T1DM onset by median 3+ years vs placebo"
  ],
  [
    "Cytokine Release Syndrome (CRS) — common during infusion; requires monitoring",
    "Lymphopenia — significant temporary reduction in lymphocyte count",
    "Rash — very common (~50% of patients during infusion course)",
    "Headache, nausea during infusion period",
    "Not a cure — only delays progression, eventual insulin dependence likely",
    "Requires inpatient or specialized infusion center setting",
    "Limited to Stage 2 T1DM (presymptomatic autoimmune disease) population",
    "Extremely high cost and limited global availability outside USA"
  ],
  "TrialNet TN10 Trial (2019/2022): 2-year delay in clinical T1DM onset; 50% of treated patients still T1DM-free at 5 years"
);

// 13. Insulin Degludec
drugSlide(
  "Insulin Degludec", "Tresiba",
  "2015 (FDA) / 2013 (EMA)", "FDA & EMA",
  "Ultra-Long-Acting Basal Insulin Analogue", C.orange,
  [
    "Insulin analogue with modified B-chain: threonine deleted at B30, C18 fatty diacid attached via linker",
    "Forms multi-hexamer chains after SC injection → soluble depot under skin",
    "Slow, continuous absorption → flat, peakless PK/PD profile",
    "Duration of action: >42 hours (truly ultra-long-acting)",
    "Reduces fasting plasma glucose with once-daily flexible dosing",
    "DEVOTE trial: significantly lower nocturnal hypoglycemia vs glargine U100",
    "Fixed combinations available: Ryzodeg (degludec + aspart 70/30)"
  ],
  [
    "Hypoglycemia — remains primary risk of all insulins (though lower than NPH/glargine U100)",
    "Weight gain — anabolic insulin effect, average 1–3 kg",
    "Injection site reactions — lipodystrophy with poor rotation technique",
    "High cost compared to biosimilar glargine or NPH",
    "No oral formulation — injection barrier for some patients",
    "Dose adjustment complexity when transitioning from other insulins",
    "Long half-life means errors in dosing have prolonged effects",
    "Biosimilar versions limited (market exclusivity)"
  ],
  "DEVOTE trial (2017): 40% reduction in nocturnal hypoglycemia vs glargine U100; non-inferior for MACE"
);

// 14. Insulin Icodec
drugSlide(
  "Insulin Icodec", "Awiqli",
  "2023 (EMA, Canada) / 2024 (FDA)", "EMA & FDA",
  "Once-Weekly Basal Insulin Analogue", C.orange,
  [
    "First once-weekly basal insulin — revolutionary dosing frequency",
    "Modified to bind reversibly to albumin via fatty acid side chains",
    "Albumin binding creates a circulating depot → slow release over 7 days",
    "Half-life ~196 hours vs ~25h for degludec or ~12h for glargine",
    "Flat, consistent PK profile → stable fasting glucose throughout week",
    "ONWARDS clinical program (6 trials): non-inferior HbA1c reduction vs daily insulins",
    "Improved adherence potential for injection-averse patients"
  ],
  [
    "Higher rate of hypoglycemia vs once-daily degludec (1.7x in ONWARDS 3)",
    "Hypoglycemia can be prolonged due to very long half-life — requires careful monitoring",
    "Loading dose required at initiation — 1.5× weekly dose in week 1",
    "Complex dose adjustment — slow titration and correction due to long half-life",
    "Not suitable for type 1 diabetes (clinical program focused on T2DM)",
    "Risk of significant glucose fluctuations if weekly injections are missed/delayed",
    "Currently limited real-world experience and long-term data",
    "Higher cost vs existing once-daily basal insulins"
  ],
  "ONWARDS 1–6 (2023): Once-weekly icodec non-inferior to once-daily degludec/glargine across diverse T2DM populations"
);

// 15. Ertugliflozin
drugSlide(
  "Ertugliflozin", "Steglatro",
  "2017 (FDA) / 2018 (EMA)", "FDA & EMA",
  "SGLT2 Inhibitor", C.sky,
  [
    "Third-generation, highly selective SGLT2 inhibitor",
    "IC50 for SGLT2 ~0.877 nM vs SGLT1 ~1000 nM (>1000-fold selectivity)",
    "Blocks ~40–50% of renal glucose reabsorption",
    "Reduces HbA1c by 0.7–1.0% at approved doses",
    "Body weight reduction ~2–3 kg",
    "Modest systolic BP reduction ~3–5 mmHg",
    "Available as monotherapy and fixed-dose combinations with metformin and sitagliptin"
  ],
  [
    "Genital mycotic infections — most common adverse effect (women > men)",
    "Urinary tract infections — class effect",
    "Volume depletion — use caution in elderly/diuretic users",
    "Euglycemic DKA — class risk",
    "VERTIS CV trial (2020): No significant reduction in MACE vs placebo (unlike empagliflozin/canagliflozin)",
    "No cardiovascular mortality benefit demonstrated — limits use vs empagliflozin/dapagliflozin",
    "Fournier's gangrene risk — class black box warning",
    "Not approved for heart failure indication"
  ],
  "VERTIS CV trial (2020): Non-inferior for MACE but no superiority; HF hospitalization reduction seen but less robust"
);

// 16. Retatrutide / Future pipeline
{
  const slide = pres.addSlide();
  addSlideBg(slide);

  slide.addShape(pres.ShapeType.rect, {
    x: 0, y: 0, w: 13.3, h: 0.55,
    fill: { color: C.yellow }, line: { color: C.yellow }
  });
  slide.addText("Triple Agonist (GIP + GLP-1 + Glucagon)  ·  Phase 3 Completed 2024  |  Under Regulatory Review", {
    x: 0.3, y: 0, w: 12.7, h: 0.55,
    fontSize: 12.5, bold: true, color: C.navy, valign: "middle", margin: 0
  });

  slide.addText("Retatrutide", {
    x: 0.4, y: 0.7, w: 9, h: 0.72,
    fontSize: 30, bold: true, color: C.white, margin: 0
  });
  slide.addText("Brand: TBD (Eli Lilly)  —  Next-Generation Triple Incretin Agonist", {
    x: 0.4, y: 1.42, w: 11, h: 0.36,
    fontSize: 13, italic: true, color: C.yellow, margin: 0
  });

  card(slide, 0.3, 1.9, 6.1, 3.0, "⚙  Mechanism of Action", C.sky, [
    "First-in-class triagonist: simultaneous GIP receptor + GLP-1 receptor + glucagon receptor activation",
    "GLP-1R activation: insulin stimulation, glucagon suppression, satiety",
    "GIPR activation: enhances insulin secretion, reduces adiposity",
    "Glucagon receptor activation: increases energy expenditure (thermogenesis), lipolysis",
    "Phase 2 data: 24.2% body weight reduction at 48 weeks (24 mg dose)",
    "HbA1c reduction up to 2.4% — unprecedented in T2DM trials",
    "Potential first-in-class for metabolic dysfunction-associated steatohepatitis (MASH)"
  ]);

  card(slide, 6.7, 1.9, 6.0, 3.0, "⚠  Anticipated Drawbacks / Phase 3 Signals", C.red, [
    "GI adverse effects more frequent than tirzepatide — nausea/vomiting/diarrhea",
    "Glucagon receptor activation raises concern for hyperglycemia rebound upon dose reduction",
    "Heart rate increase: up to 5–7 bpm (greater than GLP-1 monotherapy)",
    "Bone loss risk from glucagon receptor effects on bone metabolism",
    "Gallbladder disease: cholelithiasis risk with rapid weight loss",
    "Long-term safety unknown — regulatory approval still pending",
    "Cost expected to exceed tirzepatide given novelty",
    "Risk of muscle mass loss with aggressive weight/fat loss"
  ]);

  slide.addText("PHASE 2 (2023): 24.2% mean weight loss at 48 wks — surpassing all currently approved drugs. FDA submission anticipated 2025–26.", {
    x: 0.3, y: 5.0, w: 12.7, h: 0.35,
    fontSize: 9, color: C.gray, italic: true
  });
}

// 17. Comparative summary slide
{
  const slide = pres.addSlide();
  addSlideBg(slide);
  sectionHeader(slide, "Comparative Summary  |  Efficacy, Weight Effect & Cardiovascular Benefit");

  slide.addText("Choosing the Right Agent: Clinical Decision Guide", {
    x: 0.3, y: 0.7, w: 12.7, h: 0.45,
    fontSize: 18, bold: true, color: C.white
  });

  const criteria = [
    { cat: "Best HbA1c Reduction", drug: "Tirzepatide 15mg / Retatrutide", color: C.teal },
    { cat: "Best Weight Loss", drug: "Retatrutide ~24% > Tirzepatide 22.5% > Semaglutide 15%", color: C.green },
    { cat: "CV Mortality Benefit", drug: "Empagliflozin (EMPA-REG) > Semaglutide > Liraglutide > Dulaglutide", color: C.sky },
    { cat: "Heart Failure Benefit", drug: "Dapagliflozin / Empagliflozin (SGLT2i class)", color: C.sky },
    { cat: "Renal Protection", drug: "Canagliflozin (CREDENCE) / Dapagliflozin (DAPA-CKD)", color: C.purple },
    { cat: "T1DM Disease Modification", drug: "Teplizumab — delays onset of clinical T1DM by 3+ years", color: C.orange },
    { cat: "Simplest Weekly Dosing (Insulin)", drug: "Insulin Icodec (once-weekly SC)", color: C.orange },
    { cat: "Oral GLP-1 Option", drug: "Oral Semaglutide (Rybelsus)", color: C.green },
    { cat: "Lowest Hypoglycemia Risk", drug: "SGLT2i / GLP-1 RA / DPP-4i (all glucose-dependent)", color: C.teal },
    { cat: "Highest Safety Concerns", drug: "Canagliflozin (amputation) / SGLT2i class (DKA, Fournier's)", color: C.red },
  ];

  criteria.forEach((item, i) => {
    const row = Math.floor(i / 2);
    const col = i % 2;
    const x = 0.25 + col * 6.5;
    const y = 1.28 + row * 0.77;
    slide.addShape(pres.ShapeType.roundRect, {
      x, y, w: 6.3, h: 0.66,
      fill: { color: C.darkCard }, line: { color: item.color, width: 1.5 }, rectRadius: 0.1
    });
    slide.addShape(pres.ShapeType.roundRect, {
      x, y, w: 2.4, h: 0.66,
      fill: { color: item.color }, line: { color: item.color }, rectRadius: 0.1
    });
    slide.addText(item.cat, {
      x: x + 0.07, y, w: 2.26, h: 0.66,
      fontSize: 9, bold: true, color: C.navy, valign: "middle", margin: 0, wrap: true
    });
    slide.addText(item.drug, {
      x: x + 2.5, y, w: 3.72, h: 0.66,
      fontSize: 9.5, color: C.offWhite, valign: "middle", margin: 0, wrap: true
    });
  });
}

// 18. Closing / Key Messages
{
  const slide = pres.addSlide();
  addSlideBg(slide);

  slide.addShape(pres.ShapeType.rect, {
    x: 0, y: 0, w: 0.18, h: 5.5,
    fill: { color: C.teal }, line: { color: C.teal }
  });
  slide.addShape(pres.ShapeType.rect, {
    x: 13.12, y: 0, w: 0.18, h: 5.5,
    fill: { color: C.teal }, line: { color: C.teal }
  });

  slide.addText("Key Takeaways", {
    x: 0.5, y: 0.3, w: 12.3, h: 0.6,
    fontSize: 26, bold: true, color: C.teal, align: "center"
  });

  const points = [
    { icon: "🔵", title: "SGLT2 Inhibitors", body: "Provide CV and renal protection beyond glucose lowering. Empagliflozin and dapagliflozin are now first-line in HF/CKD. DKA, Fournier's gangrene, and amputations (canagliflozin) remain key concerns." },
    { icon: "🟢", title: "GLP-1 Receptor Agonists", body: "Semaglutide and dulaglutide offer CV mortality reduction. Weight loss is a major benefit. GI tolerability and cost remain limitations. Once-weekly injectable form preferred over daily." },
    { icon: "🟡", title: "Dual/Triple Agonists", body: "Tirzepatide (GIP+GLP-1) is best-in-class for HbA1c and weight loss in 2025. Retatrutide (GIP+GLP-1+Gcg) may surpass tirzepatide in weight reduction. Long-term safety data still accumulating." },
    { icon: "🟠", title: "Teplizumab (T1DM)", body: "Paradigm-shifting: first drug to delay T1DM onset. Targets autoimmune destruction rather than glucose alone. Limited to Stage 2 T1DM; not a cure." },
    { icon: "🟣", title: "Insulin Innovation", body: "Insulin degludec reduced nocturnal hypoglycemia. Insulin icodec (once-weekly) is the newest frontier improving adherence. Risk of prolonged hypoglycemia with long-acting insulins." },
  ];

  points.forEach((p, i) => {
    const y = 1.05 + i * 0.84;
    slide.addShape(pres.ShapeType.roundRect, {
      x: 0.4, y, w: 12.5, h: 0.72,
      fill: { color: C.darkCard }, line: { color: C.midCard }, rectRadius: 0.1
    });
    slide.addText(`${p.icon}  ${p.title}`, {
      x: 0.55, y: y + 0.04, w: 2.7, h: 0.6,
      fontSize: 11, bold: true, color: C.teal, valign: "middle", margin: 0
    });
    slide.addText(p.body, {
      x: 3.3, y: y + 0.04, w: 9.4, h: 0.6,
      fontSize: 10, color: C.offWhite, valign: "middle", margin: 0
    });
  });
}

// ─── WRITE FILE ───────────────────────────────────────────────────────────────
pres.writeFile({ fileName: "/home/daytona/workspace/diabetes-drugs-ppt/NewlyApproved_Diabetes_Drugs_2015-2025.pptx" })
  .then(() => console.log("✅ PPT created successfully!"))
  .catch(err => console.error("❌ Error:", err));