Type 2 diabetes is a condition that can affect many organs and can lead to serious complications. Recently, new classes of medications have been introduced for the treatment of Type 2 diabetes, including glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose transport protein 2 (SGLT-2) inhibitors. SGLT-2 medications increase the elimination of glucose and sodium in the urine by blocking the reuptake of filtered glucose in the kidney. GLP-1 receptor medications mimic the intestinal hormone incretin, increasing glucose-dependent endogenous insulin excretion. Both medications slow gastric emptying, decrease appetite, and regulate insulin and glucagon. Several trials have shown benefits prompting some guidelines to recommend these class of medications for patients with Type 2 diabetes (T2DM).
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The systematic review and network meta-analysis summarized here included 764 randomized trials testing SGLT-2 inhibitors or GLP-1 receptor agonists typically added to other antidiabetes medications. Trial groups received SGLT-2 or GLP-1 medications while control groups received placebos. However, both trial arms were on—and stayed on—standard background treatments that could include a variety of other medications (metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, alpha-glucosidase inhibitors, glitinides, or insulin). A total of 421,346 patients were involved in the 764 studies.
Outcomes of interest included death, nonfatal stroke, end-stage kidney disease, nonfatal heart attack, body weight change, severe hypoglycemia, severe gastrointestinal events, genital infection, ketoacidosis, amputation, and hyperkalemia. End-stage kidney disease is defined in studies as a glomerular filtration rate <15 mL/min (per 1.73 m
2) or initiation of dialysis. Tables
1 and
2 show the results found in the review. Of note, the review reports medication effects according to a patient's baseline cardiovascular risk. This is because the magnitude of the effect of diabetes medications varies according to a person's chance of developing the problem the medication is aiming to prevent. For instance, among those already at little to no risk of having a stroke, a medication's ability to demonstrate a reduction in strokes is obviously small. For those who are at higher risk of future strokes, there is a greater possibility for improvement, and effective medications can have a greater impact. Effective medications therefore tend to have different impacts in people with different risks—the higher the risk, likely the greater the impact. The authors therefore analyzed and reported medication effects separately for people in each of the following risk categories: very low (fewer than three cardiovascular risk factors), low (three or more risk factors), moderate (patients who already had known cardiovascular disease), high (those with chronic kidney disease), and very high (known cardiovascular and kidney disease).
Major harms included severe hypoglycemic episodes, severe gastrointestinal adverse events, genital infections, amputation, and ketoacidosis. SGLT-2 inhibitors increased genital infections (odds ratio [OR] 3.5, 95% confidence interval [CI] 3.0–4.0, absolute risk difference [ARD] 14%; NNH 7; high certainty). GLP-1 receptor agonists increased the risk of severe gastrointestinal symptoms (OR 2.5, 95% CI 1.2–5.0; ARD 6%; NNH 17; low certainty). There were no other differences in risks of harm between SGLT-2 inhibitors and GLP-1 receptor agonists.
Another recent review by Shi et al. conducted a similar analysis; however, it included trials comparing SGLT-2 and GLP-1 medications to standard treatments without a placebo control. After reviewing a number of original trials, we made the judgment that comparing these medications to placebo paints a more accurate picture of their effects, and we therefore used the Palmer meta-analysis as our primary source (though most relative risks in the two reviews are quite similar).
The meta-analysis by Shi et al. also, however, included trials of the new medication tirzepatide which is a glucose-dependent insulinotropic polypeptide (GIP) plus a GLP-1 medication. For completeness we are including here the weight loss impact of tirzepatide (average 8.6 kg, 95% CI 7.8–9.4 kg) and its attendant increase in severe gastrointestinal symptoms (OR 4.6, 95% CI 1.9–11.1; ARD 12.5%; NNH 8; moderate certainty), estimates from the review by Shi et al. There was no statistical difference between tirzepatide and standard treatment for all other outcomes of interest.
Importantly, when any of these medication classes were compared directly to metformin, no additional benefit was seen other than greater weight loss of varying degrees (0.2–7.7 kg).
, , However, patients on metformin had fewer genital infections and gastrointestinal adverse events.
, , While head-to-head trials are comparatively few, a large population-based study of the new medications from 2022 appears to confirm their lack of benefit over metformin, showing almost 9000 on SGLT-2 medications, when matched to over 17,000 on metformin, had identical rates of heart attack, stroke, and death but higher rates of genital infection.