Best Alternatives to Metformin: TZDs, DPP-4 Inhibitors, and Other Effective Substitutes

posted by: Adrian Harlow | on 24 May 2025

It’s one thing to get advice in a GP’s office, another when your daily life turns into a guessing game of what food you can stomach without feeling queasy from your diabetes tablets. The thing is, metformin—the number one prescription for type 2 diabetes—doesn’t agree with everyone. Some people get non-stop nausea, a run to the loo they wouldn’t wish on their worst enemy, or even rarer but nastier problems. Plenty of patients end up back at their GP saying, ‘Isn’t there something else?’ Good news: there are real alternatives and some work just as well as metformin, sometimes even better, if you pick what’s right for your body.

Why Do People Need Metformin Alternatives?

The NHS has prescribed metformin for decades because it’s effective, cheap, and well-researched. But there’s a catch if you’re one of the 20% of people who can’t tolerate it, often due to gut-related side effects like diarrhoea, cramping, or flat-out nausea. Sometimes it’s more serious—rare but real cases of lactic acidosis or vitamin B12 deficiency. Even with slow-release formulas, sometimes metformin and your body simply don’t get along. Maybe you’ve noticed that changes in diet or timing haven’t solved your symptoms, or you’re part of the smaller group with kidney or liver issues, where metformin triggers more risks than benefits.

If you’ve tried all the fixes—splitting doses, taking with food, asking your chemist for extended-release tablets—and you’re still struggling, switching meds might be the only way to keep your life on track. Others just want options that fit better with other meds, fewer worries about hypoglycaemia, or maybe something less likely to mess with the stomach. You aren’t alone, and this is why the world of diabetes treatments keeps growing.

Spotlight: TZDs (Thiazolidinediones) Explained

TZDs—or thiazolidinediones if you love tongue twisters—have actually been around since the 1990s. The most used in the UK today is pioglitazone. These pills work by making your body more sensitive to insulin, which drops your blood sugar by helping your cells absorb more glucose. Unlike metformin, TZDs don’t usually cause stomach upset. Instead, their most common side effects can be weight gain, ankle swelling, and sometimes a mild risk of heart-related troubles. Here’s a neat table breaking down common differences:

If your stomach revolts on metformin but your main concern is cholesterol or heart disease, TZDs like pioglitazone can sometimes help there too—they actually offer some improvement in “good” cholesterol (HDL). These drugs are simple—a single daily pill, food or no food. Some GPs may avoid them with patients who have heart failure or fractures in their medical past, because they can make those risks a bit worse. Not perfect, but for many, a relieve-the-belly, once-a-day solution.

DPP-4 Inhibitors: Gentler, Modern Alternatives

Imagine a diabetes med that lets you eat, work, and sleep without side effects ambushing you every few hours. That’s why DPP-4 inhibitors, or “gliptins,” such as sitagliptin or linagliptin, get prescribed more these days, especially for older patients or those with sensitive guts. These tablets target a different pathway—they let your own body increase insulin only when needed, which means the risk of low blood sugar is pretty slim on their own.

DPP-4 inhibitors tick all the boxes if you hate forced meal schedules and want a med that doesn’t make you gain weight. Unlike metformin, there’s no metallic aftertaste, no rushing to toilets, and they’re usually fine to use if your kidneys aren’t perfect. Of course, not every box is green—some people get headaches or joint pain, and, rarely, pancreatitis. Most stay side-effect-free though. These tablets won’t make your sugars drop as dramatically as injected GLP-1 agonists do, but for thousands each year in the UK, it’s a fair trade-off for a calmer day.

If you want a deeper dive into prescription and natural options, you can find a handy roundup of substitutes for metformin with plain-English breakdowns—worth a look if you want to put all choices on the table.

SGLT2 Inhibitors, Sulfonylureas, and Less Common Choices

Another alternative on the rise, especially if you’re already struggling with blood pressure or want to shed a few kilos, is the SGLT2 inhibitor group. Dapagliflozin and empagliflozin make you pee out extra sugar; bonus, they help with heart and kidney disease, as plenty of UK trials now show. You’ve probably seen TV ads mentioning these for heart failure or chronic kidney disease, because they genuinely help with those. The main downside: risk of minor infections ‘down below’ since urine gets more sugary. Drinking more water, keeping clean, and knowing the signs can help.

Then there are sulfonylureas—older tablets like gliclazide and glimepiride. They’re cheap, work fast, and are often prescribed for people whose sugars need a sharp drop. The catch is they can cause weight gain and sometimes push blood sugar too low, which is scary if you live alone or have a busy job. It’s old-school medicine, but still prescribed especially for people who are slim and have a long way to go with diet and exercise changes.

Injections, like GLP-1 receptor agonists (semaglutide, liraglutide), are less common first-line choices but can be a game-changer if you want both weight loss and strong blood sugar drops. But they require injections—never everyone’s cup of tea. There’s also a patchwork of “meglitinides” and “alpha-glucosidase inhibitors,” but these are falling out of fashion thanks to newer, milder drugs. The choice is always unique to your daily life and what you’re willing (or able) to try. No solution is one-size-fits-all.

Choosing What’s Right: Tips for Navigating the Maze

No decision about diabetes meds should happen in a vacuum. If your current metformin script is making life miserable, it’s never a bad idea to ask your GP if they’ve considered DPP-4 inhibitors, SGLT2 inhibitors, or even a TZD. Chat with friends or support group members—real stories sometimes reveal gaps in what gets discussed in hurried office visits. Keep a quick diary of your side effects—exact times, what you ate, and how long symptoms last. It’ll help your doctor make a decision you trust.

The NHS does base its guidelines on strong evidence but lets your own lifestyle and priorities matter too. For example, if you’re a night-shift worker in Manchester who doesn’t eat regularly, a sulfonylurea could mess up your sleep or risk nighttime hypos—but a DPP-4 inhibitor might stitch into your schedule better. If weight gain is something you dread, avoiding TZDs or sulfonylureas makes sense, so you might steer towards SGLT2 inhibitors or GLP-1s. If cost or prescription coverage is a factor, ask outright which meds are covered or have discount options in your area.

• Track any new meds for side effects for the first two weeks—this can help you spot patterns early.
• Don’t swap or stop meds before checking in with a GP, as stopping suddenly can spike your sugars fast.
• Mixing some diabetes meds with others (like insulin) can drop sugars too much—always clarify interactions before adding anything new.
• Some GPs are more up on the latest drug trends than others—ask if your surgery has a diabetes nurse specialist.

At the end of the day, you want treatment that works with you, not against you. That might look different for everyone, but there’s no shame in asking about other options when metformin just isn’t playing nicely. Stay informed and keep those questions coming—because no one knows your daily experience better than you.