Type 2 Diabetes Medications Beyond GLP-1 Drugs: What the Evidence Shows

GLP-1 medications get most of the attention in conversations about type 2 diabetes right now, but they are only one part of a much larger toolbox. Metformin, SGLT2 inhibitors, sulfonylureas, DPP-4 inhibitors, thiazolidinediones, and insulin all have decades of data behind them, and for many people, one of these medications, or a combination, is what actually gets blood sugar to a safe range. The right choice depends on your kidneys, your heart history, your budget, and how your body responds. Here is what the evidence actually shows about each class.

Metformin: still the starting point for most people

Metformin has been the default first medication for type 2 diabetes for a long time, and the evidence still supports that. In the UK Prospective Diabetes Study, patients treated with metformin had a 32 percent reduction in diabetes-related endpoints and a 36 percent reduction in all-cause mortality compared with conventional diet-based treatment, with less weight gain and fewer low blood sugar episodes than insulin or sulfonylureas (UKPDS 34, Lancet, 1998). It is inexpensive, taken as a pill, and roughly weight neutral. The most common downside is gastrointestinal upset, which usually improves with a slow dose increase or an extended-release formulation. Kidney function needs to be checked periodically, since dosing is adjusted as it declines.

SGLT2 inhibitors: benefits that go beyond blood sugar

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which include empagliflozin (Jardiance) and dapagliflozin (Farxiga), work by causing the kidneys to excrete excess glucose in the urine. What made this class notable is not just glucose control. In the EMPA-REG OUTCOME trial, empagliflozin reduced cardiovascular death by 38 percent and all-cause death by 32 percent in people with type 2 diabetes and existing heart disease, compared with placebo (Zinman et al., NEJM, 2015). Separately, the DAPA-CKD trial found that dapagliflozin reduced the risk of kidney disease progression or cardiovascular death by 39 percent in people with chronic kidney disease, whether or not they had diabetes (Heerspink et al., NEJM, 2020). That dual benefit is why this class is often used even when blood sugar alone would not require it. The tradeoffs include a higher risk of genital yeast infections and, rarely, a serious complication called diabetic ketoacidosis, so we talk through the warning signs before starting.

Sulfonylureas: effective, cheap, and worth understanding the risks

Sulfonylureas, such as glipizide and glimepiride, stimulate the pancreas to release more insulin. They lower A1C about as much as many newer drugs and cost very little, which matters for people without generous drug coverage. The real tradeoff is hypoglycemia. Because these drugs push insulin release regardless of how much glucose is actually in the blood, low blood sugar is a genuine risk, especially in older adults, people with irregular eating patterns, or those with reduced kidney function. Modest weight gain is common too. For someone who needs an affordable, effective add-on and can manage the hypoglycemia risk, this class still has a place.

DPP-4 inhibitors: a gentler, more modest option

DPP-4 inhibitors, including sitagliptin (Januvia) and linagliptin (Tradjenta), work through the same incretin pathway as GLP-1 medications, but more mildly. They are taken as a once-daily pill, are generally well tolerated, and do not typically cause hypoglycemia on their own. A recent Cochrane review of people with chronic kidney disease and type 2 diabetes found DPP-4 inhibitors had little effect on hypoglycemia risk requiring assistance, compared with placebo (Natale et al., Cochrane Database Syst Rev, 2025). The main limitation is that they lower A1C less than most other classes, often around 0.5 to 0.8 percentage points, so they are frequently used as an add-on rather than a primary treatment.

Thiazolidinediones: real benefits, real tradeoffs

Pioglitazone is the main thiazolidinedione still used today. It improves insulin sensitivity in muscle and fat tissue rather than increasing insulin supply, and it can be a reasonable option for people with significant insulin resistance. The tradeoff that matters most is bone health. A 2025 systematic review and meta-analysis found pioglitazone was associated with a meaningfully increased fracture risk, particularly in women and in the lower extremities (Azhari and Dawson, Front Pharmacol, 2025). It can also cause fluid retention and weight gain, so we use it selectively, with an honest conversation about who it fits and who it does not.

Insulin: not a last resort, but a tool used when it is needed

Type 2 diabetes often involves a gradual decline in the pancreas's own insulin production, and for some people, insulin eventually becomes part of the picture, sometimes alongside oral medications rather than replacing them. Modern basal insulins are designed to be taken once daily with a relatively predictable, gentle action profile. The tradeoffs are weight gain and a hypoglycemia risk that requires some monitoring, along with the practical step of learning to give an injection. None of that means treatment has failed. It means the medication has been matched to what your body needs at this point in your care.

Finding the right combination for you

Most people end up on more than one of these medications over time, chosen based on kidney function, heart history, weight goals, cost, and how blood sugar actually responds. If you are managing type 2 diabetes and want a plan built around your actual labs and history, not a one-size-fits-all protocol, our endocrinology care is available by telehealth appointment in every state we are licensed in. Most major plans are accepted, including Medicare, so getting this kind of care does not have to be something you pay for separately from the coverage you already have.