Modern Type 2 Diabetes Therapy: Choosing Drugs by Organ Risk

1. Slide 1 · Type 2 Diabetes: Modern Glucose-Lowering Therapy

   Type 2 Diabetes: Modern Glucose-Lowering Therapy

   Metformin, SGLT2 inhibitors and GLP-1 RAs matched to heart and kidney risk

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   Speaker notes

   Welcome, everyone. Today we will build up type 2 diabetes treatment step by step. We start with what the disease is and how we diagnose it. Then we look at the three drug classes you will prescribe most often: metformin, SGLT2 inhibitors and GLP-1 receptor agonists. The key shift of the last decade is that we no longer choose drugs only to lower HbA1c. We choose them to protect the heart and the kidneys. By the end, you should be able to look at a patient with heart failure, CKD or atherosclerotic disease and know which drug to start, and why.

2. Slide 2 · T2D: insulin resistance plus failing beta cells

   T2D: insulin resistance plus failing beta cells

   Chronic hyperglycaemia from insulin resistance and progressive beta-cell dysfunction

   Muscle and liver resist insulin; hepatic glucose output rises

   Beta-cell function declines over time, so therapy usually needs escalation

   Reduced incretin effect, raised glucagon and renal glucose reabsorption contribute

   Strongly linked to obesity, inactivity, family history and ageing

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   Speaker notes

   Let's define the disease. Type 2 diabetes is chronic hyperglycaemia driven by two problems together: insulin resistance in muscle, liver and fat, and beta cells that progressively fail to compensate. Several organs contribute. The liver overproduces glucose, the gut produces less incretin effect, alpha cells release too much glucagon, and the kidneys keep reabsorbing glucose. Here is the useful trick: each drug class we discuss targets one of these organs. Metformin acts mainly on the liver, GLP-1 agonists on the incretin system, SGLT2 inhibitors on the kidney. And because beta-cell failure is progressive, explain to patients early that adding drugs over time is expected, not a personal failure.

3. Slide 3 · Diagnosis: four criteria, confirm unless clearly symptomatic

   Diagnosis: four criteria, confirm unless clearly symptomatic

   Test	Diabetes threshold	Practical note
   HbA1c	≥6.5% (48 mmol/mol)	Unreliable with anaemia, haemoglobinopathy, pregnancy
   Fasting plasma glucose	≥126 mg/dL (7.0 mmol/L)	At least 8 hours fasting
   2-hour OGTT (75 g)	≥200 mg/dL (11.1 mmol/L)	Most sensitive, less convenient
   Random plasma glucose	≥200 mg/dL (11.1 mmol/L)	Only with classic hyperglycaemia symptoms

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   How do we make the diagnosis? There are four accepted criteria. HbA1c of 6.5 percent or more, fasting glucose of 126 milligrams per decilitre or more, a two-hour value of 200 or more on the 75-gram glucose tolerance test, or a random glucose of 200 or more with classic symptoms such as polyuria, polydipsia and weight loss. Without symptoms, confirm with a repeat test. A practical pitfall: HbA1c misleads when red cell turnover is abnormal, for example in anaemia, haemoglobinopathies or pregnancy. In those patients, rely on glucose-based tests. Also, always ask yourself whether this could be type 1 or LADA, especially in a lean, younger patient losing weight.

4. Slide 4 · From glucose control to organ protection

   From glucose control to organ protection

   How outcome trials changed drug selection

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   Now we move into management. For decades, treatment decisions were driven by glucose levels: start metformin, then add whatever lowered HbA1c next. Large cardiovascular and kidney outcome trials changed that. SGLT2 inhibitors and GLP-1 receptor agonists reduced cardiovascular events, heart failure and kidney disease progression, and these benefits are largely independent of their glucose-lowering effect. So the modern question is not only 'how high is the HbA1c?' but 'what organ is this patient most likely to lose?' Let's first compare the three drug classes side by side.

5. Slide 5 · Three core drug classes at a glance

   Three core drug classes at a glance

   Class	Main mechanism	Key strengths	Main cautions
   Metformin	Reduces hepatic glucose production	Cheap, weight neutral, low hypoglycaemia risk	GI upset, B12 deficiency, avoid if eGFR <30
   SGLT2 inhibitors	Block renal glucose reabsorption	Heart failure and kidney protection, weight loss	Genital infections, euglycaemic DKA, volume depletion
   GLP-1 receptor agonists	Glucose-dependent insulin release, less glucagon, satiety	ASCVD protection, potent glucose and weight lowering	Nausea, vomiting; injectable or oral

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   Speaker notes

   Here are the three classes side by side. Metformin works mainly in the liver; it is inexpensive, does not cause weight gain and rarely causes hypoglycaemia on its own. Watch for GI side effects, check B12 over time, and stop it when eGFR falls below 30. SGLT2 inhibitors make the kidney excrete glucose and sodium; their real value is heart failure and kidney protection. GLP-1 receptor agonists boost glucose-dependent insulin secretion, suppress glucagon and reduce appetite, giving strong HbA1c and weight reduction plus cardiovascular benefit. Tip for exams and wards: none of these three causes much hypoglycaemia alone, unlike sulfonylureas and insulin.

6. Slide 6 · SGLT2 inhibitors protect heart and kidneys

   SGLT2 inhibitors protect heart and kidneys

   −23%

   CV death or heart failure hospitalisation (HR 0.77)

   −11%

   MACE, benefit seen only with established ASCVD

   −38%

   CKD progression across eGFR strata (HR 0.62)

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   Let's look at the evidence for SGLT2 inhibitors. In a Lancet meta-analysis of cardiovascular outcome trials, they reduced cardiovascular death or heart failure hospitalisation by 23 percent. Major adverse cardiovascular events fell by 11 percent, but only in patients with established atherosclerotic disease. The kidney story is even stronger: a 2026 JAMA meta-analysis of over 70,000 participants showed a 38 percent reduction in CKD progression, consistent across eGFR categories. In patients with CKD specifically, they also lowered heart failure and slowed eGFR decline. Memorable takeaway: think SGLT2 inhibitor first for heart failure and for kidneys, regardless of HbA1c.

7. Slide 7 · GLP-1 RAs: strongest for atherosclerotic risk

   GLP-1 RAs: strongest for atherosclerotic risk

   Reduce MACE by about 21%, consistent with or without SGLT2 inhibitors

   Injectable semaglutide lowered MACE in SUSTAIN-6 (HR 0.74)

   Oral semaglutide reduced MACE in high-risk patients (SOUL, HR 0.86)

   FLOW: semaglutide cut major kidney events by 24% in T2D with CKD

   Tirzepatide (GIP/GLP-1) produces large weight loss in T2D with obesity

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   Speaker notes

   Now GLP-1 receptor agonists. A 2024 Circulation meta-analysis showed a 21 percent reduction in major adverse cardiovascular events, and importantly the effect was similar whether or not patients already took an SGLT2 inhibitor, so the two classes can be combined. SUSTAIN-6 showed injectable semaglutide reduced MACE, driven largely by fewer strokes. The SOUL trial extended cardiovascular benefit to oral semaglutide. FLOW was the first dedicated kidney outcome trial for this class, with a 24 percent reduction in major kidney events. Finally, tirzepatide, a dual GIP and GLP-1 agonist, gives substantial weight loss in people with type 2 diabetes and obesity.

8. Slide 8 · Choose the drug by the patient's dominant risk

   Choose the drug by the patient's dominant risk

   Clinical profile	Preferred choice	Comment
   Heart failure	SGLT2 inhibitor	Benefit independent of HbA1c
   CKD	SGLT2 inhibitor plus metformin if eGFR ≥30	KDIGO: SGLT2i if eGFR ≥20; add GLP-1 RA if needed
   Established ASCVD	GLP-1 RA or SGLT2 inhibitor	Strongest recommendation when ASCVD and CKD coexist
   Obesity as main priority	GLP-1 RA or tirzepatide	Greatest weight reduction
   No CVD, CKD or high risk	Metformin, individualise	Weigh cost, preference, hypoglycaemia risk

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   Speaker notes

   This is the slide to remember. Start by asking which organ is most at risk. Heart failure: SGLT2 inhibitor. Chronic kidney disease: KDIGO 2022 recommends an SGLT2 inhibitor when eGFR is at least 20, and metformin when eGFR is at least 30, adding a GLP-1 agonist when more glucose lowering or protection is needed. Established atherosclerotic disease: GLP-1 agonist or SGLT2 inhibitor. The BMJ guideline gives a strong recommendation for SGLT2 inhibitors when CVD and CKD coexist. For lower-risk patients, metformin remains a sensible, affordable start. Practical tip: in high-risk patients, do not wait for metformin to fail before adding an organ-protective drug.

9. Slide 9 · Safety pearls before you prescribe

   Safety pearls before you prescribe

   SGLT2 inhibitors

   Counsel on genital hygiene; mycotic infections are common

   Sick-day rule: pause during acute illness, fasting or surgery

   Watch for euglycaemic DKA, even with near-normal glucose

   Expect a small early eGFR dip; do not stop for it

   GLP-1 receptor agonists

   Start low, titrate slowly to limit nausea and vomiting

   Check retinopathy if HbA1c will fall rapidly

   Avoid with medullary thyroid cancer or MEN2 history

   Stop if pancreatitis is suspected

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   Speaker notes

   Before prescribing, know the practical safety points. For SGLT2 inhibitors, warn patients about genital fungal infections and hygiene. Teach sick-day rules: pause the drug during vomiting, poor intake or before surgery, because euglycaemic ketoacidosis can occur with near-normal glucose. A small eGFR drop in the first weeks is expected and haemodynamic, so do not stop the drug. For GLP-1 agonists, start at a low dose and titrate slowly to limit GI effects. In SUSTAIN-6, retinopathy complications were more frequent with semaglutide, so check the eyes in patients with existing retinopathy. Avoid in medullary thyroid cancer or MEN2 history.

10. Slide 10 · References

    References

    1. 1.Li S, Vandvik PO, Lytvyn L, et al. SGLT-2 inhibitors or GLP-1 receptor agonists for adults with type 2 diabetes: a clinical practice guideline. BMJ. 2021. doi:10.1136/bmj.n1091
    2. 2.Navaneethan SD, Zoungas S, Caramori ML, et al. Diabetes Management in Chronic Kidney Disease: Synopsis of the KDIGO 2022 Clinical Practice Guideline Update. Ann Intern Med. 2023. doi:10.7326/M22-2904
    3. 3.Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019. doi:10.1016/S0140-6736(18)32590-X
    4. 4.Neuen BL, Fletcher RA, Anker SD, et al. SGLT2 Inhibitors and Kidney Outcomes by Glomerular Filtration Rate and Albuminuria: A Meta-Analysis. JAMA. 2026. doi:10.1001/jama.2025.20834
    5. 5.Toyama T, Neuen BL, Jun M, et al. Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis. Diabetes Obes Metab. 2019. doi:10.1111/dom.13648
    6. 6.McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis. JAMA Cardiol. 2021. doi:10.1001/jamacardio.2020.4511
    7. 7.Nuffield Department of Population Health Renal Studies Group, SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022. doi:10.1016/S0140-6736(22)02074-8
    8. 8.Neuen BL, Fletcher RA, Heath L, et al. Cardiovascular, Kidney, and Safety Outcomes With GLP-1 Receptor Agonists Alone and in Combination With SGLT2 Inhibitors in Type 2 Diabetes: A Systematic Review and Meta-Analysis. Circulation. 2024. doi:10.1161/CIRCULATIONAHA.124.071689
    9. 9.Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016. doi:10.1056/NEJMoa1607141
    10. 10.McGuire DK, Marx N, Mulvagh SL, et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. N Engl J Med. 2025. doi:10.1056/NEJMoa2501006
    11. 11.Perkovic V, Tuttle KR, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024. doi:10.1056/NEJMoa2403347
    12. 12.Mann JFE, Rossing P, Bakris G, et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med. 2024. doi:10.1038/s41591-024-03133-0
    13. 13.Garvey WT, Frias JP, Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023. doi:10.1016/S0140-6736(23)01200-X
    14. 14.Rossing P, Caramori ML, Chan JCN, et al. Executive summary of the KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease: an update based on rapidly emerging new evidence. Kidney Int. 2022. doi:10.1016/j.kint.2022.06.013

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11. Slide 11 · Questions?

    Questions?

    Treat the organ at risk: SGLT2i for heart failure and kidneys, GLP-1 RA for atherosclerosis

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    Speaker notes

    To wrap up, three takeaways. First, type 2 diabetes is a progressive, multi-organ disease, so escalation is expected. Second, metformin is still a reasonable, affordable foundation, especially in lower-risk patients. Third, and most important, choose add-on therapy by the organ at risk: SGLT2 inhibitors for heart failure and CKD, GLP-1 receptor agonists for atherosclerotic disease and obesity, and both together when risk is high. Refer to endocrinology or nephrology when targets are not met despite combination therapy, eGFR is falling quickly, or the diagnosis is uncertain. Thank you, and I am happy to take your questions.

This presentation was generated automatically to show what Doctoria can do and has not been reviewed as clinical guidance. Clinical cases in the examples are fictional.